Autophagy up-regulation by ulipristal acetate as a novel target mechanism in the treatment of uterine leiomyoma: an in vitro study

Objective: To assess the effect of ulipristal acetate (UPA) on the autophagic process of uterine leiomyoma cells. Design: In vitro study in primary cultures of leiomyoma and myometrial cells isolated from biopsy specimen, and gene expression evaluation in biopsy material. Setting: Cellular pathology laboratory. Patient(s): Premenopausal women (without hormonal treatment) undergoing myomectomy or hysterectomy for symptomatic leiomyomas. Intervention(s): Surgical specimens collected from uterine leiomyomas and matched normal myometria. Main Outcome Measure(s): After treatment of myometrial and leiomyoma cells with UPA, autophagy was evaluated by Western blot analysis of the typical biochemical markers, LC3-II, LC3-II:LC3-I ratio, and p62/SQSTM1. The expression level of Atg7 and Atg4D proteins was also assessed by Western blot. Result(s): The increase of LC3-II protein, LC3-II:LC3-I ratio, and p62/SQSTM1 protein indicates that UPA treatment up-regulates the autophagic response in leiomyoma cells, whereas these markers were almost unchanged in myometrial cells. Consistently, an increased level of Atg7 and Atg4D proteins was observed only in UPA-treated leiomyoma cells. The autophagic machinery is put into motion selectively in these cells, despite that the basal messenger RNA levels of LC3, SQSTM1, and ATG7 in leiomyoma biopsy specimen were not significantly different from those found in normal myometrial biopsy material. Conclusion(s): In vitro UPA treatment stimulates the autophagic response selectively in leiomyoma cells, which adds a novel indication for the clinical use of this selective P receptor (PR) modulator. Autophagy up-regulation may potentially contribute to the leiomyoma shrinkage occurring in UPA-treated patients and warrants further study.